DyslipidemiaMondayPart2lecture

Question 1

Omega(w)-3 Fatty Acids - Cardioprotective

What five things do they decrease?

What two things do they increase?

Answer 1

Omega-3 Fatty Acids are Cardioprotective

They DECREASE:

• Blood triacylglycerol (high doses)
• Thromboxane A2 synthesis (and thus inflammation)
• Platelet adhesion
• Ischemic myocardial damage
• Restenosis after angioplasty (high doses)
• in email Goodridge said they decrease LDL-C as well (this was a clicker question)

The INCREASE:

• Nitric oxide production
• RBC membrane fluidity

Question 2

Dietary Sources of Omega(w)-3 Fatty Acids

Answer 2

• Nut and seed oils
• Canola oil
• OILY FISH (herring, salmon, sardines, tuna)
• Shell fish (oysters, crab)

Question 3

Question: Cardioprotective effects of dietary w-3 Fatty Acids may be due to which of the following?

A) Decreased synthesis of thromboxane A2
B) Increased fluidity of erythrocyte membranes
C) Decreased platelet adhesion
D) All of the above
E) B and C Only

Answer 3

Answer: D) All of the above

Cardioprotective effects of dietary w-3 Fatty Acids may be due to all:

-Decreased synthesis of thromboxane A2, Increased fluidity of erythrocyte membranes, and decreased platelet adhesion.

(Note: other slide shows they do a few more things. They ecrease blood triacylglycerol (at high doses) and decrease restenosis after angioplasty (at high doses). They also increase Nitric Oxide Production.)

Question 4

Sources of Omega-3 Fatty Acids?

Hint: Are they made from animal tissues or not? If not, what makes it and how do we get it?

Answer 4

Omega 3 Fatty Acids are NOT made by animal tissues.

Omega 3 Fatty Acids are synthesized/made/produced by ALGAE!

These algae are eaten by small marine animals, which are eaten by fish, and then humans eat the fish to get Omega-3 Fatty Acids.

This is a case where the algae in water is a good thing/positive effect, because it leads to production of Omega-3 Fatty Acids.

Question 5

Supplements with w-3 Fatty Acids

Answer 5

Supplement w-3 FA content

Max-EPA capsules 0.3 gm/capsule (1ml)

Flaxseed Oil (50% w-3)           7.3 gm/TBSP  
                                              (alpha lenolenic) (18:3)

Salmon Oil (14% w-3) 1.9 gm/TBSP (EPA and DHA)

***Omacor (85% w-3) 900 mg EPA/DHA/Capsule

***Note: Omacor has greatest amount (most potent in w-3) and has combination of EPA and DHA
EPA= eicosapentaenoic acid (20:5)
DHA= docosahexaenoic acid (22:6) with 900mg per capsule

Question 6

Effects of w-3 Fatty Acid Supplements on Serum Lipids in study with patients who were on Statins

Answer 6

Before After p-value

Triglyceride 400 +/- 91 261 +/- 48 0.0005

LDL Cholesterol 135 +/- 54 127 +/- 56 NS

HDL Cholesterol 42 +/- 15 39 +/- 12 NS

Summary:

Omega-3 Fatty Acids lowered Triglycerides (2 mg Omacor) in this study with patients already taking simvastatin, but w-3 FA didn’t have significant effect on cholesterol levels (only because they were on statins).

However, author of study said that “these anti-inflammatory omega-3’s were associated with a 43 percent INCREASE RISK FOR PROSTATE CANCER overall, and a 71% INCREASE RISK IN AGGRESSIVE PROSTATE CANCER”

Question 7

Why were all the subjects still taking simvastatin when test with Omega-3 experiment?

Answer 7

Because it’s unethical to withhold effective treatment of CHD when testing treatments of unknown effectiveness.

Question 8

Alcoholic Beverages

Answer 8

• Decrease Coronary Arteries (1-2 drinks/day, so at moderate consumption)
• Mechanisms:
  *Increase HDL cholesterol 5-8% (so small amount)
  *Decrease platelet adhesion
  *Antioxidant (?, maybe, like resveratrol in red wine)
  *Reduce stress (?, maybe, but downside is it’s
  addictive so be careful and wouldn’t be
  recommended to non-drinkers for this reason)
• Increase Blood Triglyceride (so this is BAD about alcohol)
  • Ethanol —> acetate —-> acetly-CoA —> FA
    
    • —-> triglyceride (liver)

*Resveratrol has effect because of skin of red grapes, so grapejuice has it. Problem is that you would need resveratrol supplement, because amount you need would be 3 Liters of Wine per day to have clinical effect!!! Also other foods such as Peanuts contain resveratrol so it’s not just on the skin of grapes (but peanuts don’t have as much as a glass of red wine). However, it’s not used unless supplement form for clinical uses for the reason of high amount required.

Question 9

Potential Beneficial Biological Activities of Resveratrol

Answer 9

Resveratrol benefits:

-Anti-inflammatory
-Inhibits expression of vascular cell adhesion molecules
-Inhibits vascular smooth muscle cell proliferation
-Stimulates endothelial nitric oxide synthase (eNOS)
activity
-Inhibits platelet aggregation

Question 10

Which breakfast food should lower plasma cholesterol?

A) Eggs C)Flank steak
B)Deep Dish Pizza D)Smoked Salmon
E)Yogurt F) Butter Croissant

Answer 10

Answer: D) SMOKED SALMON

Smoked Salmon will lower plasma cholesterol

(Ask him why?)

Question 11

Drugs (other than Statins) that are used to treat High LDL Cholesterol Level:

Niacin

Answer 11

Niacin

• Nicotinic acid (2g/d)
• Reduced LDL-cholesterol and triglycerides
• Raises HDL-cholesterol
• Independent of function as vitamin (Recommended Daily Allowance/RDA is 14-16mg/d so this is a high dose for treatment and works through independent mechanism)
• Decreases lipoprotein synthesis and production of VLDL (so therefore less LDL will be formed as well)
• Decreases mobilization of unesterified fatty acids from periphery
• May not be well tolerated at high doses (patients need to have liver enzymes monitored to see if the high dose is too toxic for their liver, and watch for jaundice to see if liver is effected too much)

Question 12

Drugs (other than Statins) that are used to treat Cholesterol Level:

Fibrates

Answer 12

Fibrates are used to treat hypercholesterolemia, because they increase HDL and decrease triglycerides. They actually have little or no effect on lowering LDL.

Fibrates:

• Decrease triglycerides
• Little or no effect on LDL-cholesterol
• Increase HDL-cholesterol
• Agonists for PPARalpha, a transcription factor for several genes in lipid metabolism
• May increase morbidity (non-coronary heart disease)

Note: Fibrates looks similiar/mimic structure of Fatty Acid because they have hydrophilic side and long hydrophobic region, so that’s probably how they work.

(So the last item is the major downside: it can cause other unrelated problems that increase risk of death)

Sidenote: PPAR = peroxisome proliferator-activated receptor, because peroxisomes are where fatty acids are oxidized…but you don’t need to know the long version of this name, just know PPARalpha for Fibrates

Question 13

Note card summary of drug table (see actual table for details)

Answer 13

Drugs Used to Treat Dyslipidemia: Effects on Blood Lipids

-STATINS are MOST-EFFECTIVE/best for LOWERING LDL-cholesterol (18-55% decrease), they also cause small increase in HDL-cholesterol and small decrease in triglycerides

The rest of the the drugs have much SMALLER effects than statins:

• Niacin is best after statins, mainly because it’s good/better at INCREASING HDL-cholesterol (15-35% increase), and it also lowers LDL and triglycerides
• Fibrates don’t really effect LDL-cholesterol, but they LOWER HDL-cholesterol and triglycerides
• Bile Acid Sequesterants (BAS) are lipid sequesterants that bind bile acids to therefore increase excretion of cholesterol in stool. These don’t really effect HDL-cholesterol (or triglycerides) but they DECREASE LDL-cholesterol somewhat.

Ezitimibe inhibits cholesterol transporter that normally takes cholesterol from lumen of intestine into the enterocyte (it inhibits the NP-whateverprotein). It DECREASES LDL-cholesterol somewhat.

Question 14

Two NEW Potent cholesterol-lowering drugs get FDA advisory approval:

Alirocumab (Praluent) and Evolocumab (Repatha)

Hint: ending in “mab” means it’s monoclonal antibody

Answer 14

Alirocumab (Praluent) and Evolocumab (Repatha) are monoclonal antibodies that bind to and INHIBIT activity PCSK9

Don’t worry about what PCSK9 stands for, but know how PCSK9 works. Separate card discusses PCSK9 mechanism.

Question 15

PCSK9 Mechanism of Action

Answer 15

Two ways to inhibit the recycling of the LDL-recepor (LDL-R):

PCSK9 and LDL-receptor are made in ROUGH ER and then packaged in golgi. If PCSK9 is bound to the LDL-receptor in the golgi this will target it to lysosomes and get degraded. Otherwise, both go to surface and LDL receptor stays bound to membrane while PCSK9 gets released. The PCSK9 in blood cannot bind to VLDL but it can bind to LDL and if it binds to LDL it can block the binding of LDL to the LDL-receptor. More importantly, when PCSK9 binds to the LDL-receptor directly (without any LDL), it targets the LDL-receptor for degradation (in lysosomes).

The monoclonal antibodies bind to PCSK9 and prevent it from binding to LDL-receptor. This therefore increases recycling of LDL-receptor, making more LDL-receptor recycled (goes to) the surface because it is not degraded. So this is a very effective drug.

The Drug is in Pen and the needle is INJECTED SUBCUTANEOUSLY to the patient.

Question 16

DESCARTES: PCSK9 drug study with % change on various patients (using diet, statins, etc, and testing this drug) to see if it lowers LDL-C

Answer 16

Every single circumstance had additional decrease in LDL-C by 50-60 percent! This shows PCSK9 is very effective!

Downside is that PCSK9 drugs have very short half-life, so you need to inject about every 2 weeks. A one-month supply costs about 2000-2500 dollars! So if you can get treatment with atorvastatin (generic statin drug) to lower LDL-C in good enough amount, there’s no need to spend so much money to use this more lowering of LDL-C.

However, for certain things it is covered by insurance and used more often (specifically approved by FDA for these things). These are people with “familial hypercholesteremia” or people who “have had a heart attack or stroke”.

Question 17

Heterozygous Familial Hypercholesterolemia

Answer 17

Phenotype
-LDL-C is twice normal (190-350 mg/dL)
-Premature coronary heart disease is common
(these ppl have heart attacks in late 30s, 40s, 50s, which is much earlier and uncommon for normal ppl)

Genotype

  - Mutation in LDL-receptor gene (ONE allele)
  - this can be caused by a variety of different mutations that alter the gene

Prevalance
-1 in 500 (USA)

Treatment
-TLC + Statins + Bile acid sequesterants and/or niacin if necessary, and now PCSK9 inhibitor (it is approved for this disease to be covered by insurance)

Note: TLC= therapeutic lifestyle changes (diet, exercise)

Question 18

Homozygous Familial Hypercholesterolemia

Answer 18

Phenotype

  - LDL-cholesterol levels increase 4-fold (400-1000mg/dL)
   - Widespread severe atheroschlerosis (these people have heart attacks VERY EARLY in life like in the TEENAGE YEARS)

Genotype

   - Mutation in LDL Receptor Gene (BOTH alleles)
   - This doesn't have to be same mutation; it could be different mutations for each allele, but it has to be mutations on both of the alleles and consequence is the same (no LDL receptor for this disease!)

Prevalence
-1 in 1 million (USA) so it’s very rare

Treatment
-Statins, statins + niacin; LDL-pheresis; Liver transplant, nothing else very effective

• Liver transpant helps because NEW LIVER won’t have the same defective genes and can make the proper LDL receptors
• LDL-pheresis is taking blood out, removing LDL, and then putting the blood back into the patient (since high LDL is the problem)

Note: in this case PCSK9 is not effective for treatment, because it would just increase recycling of LDL receptor and cause more to be on the cells. This wouldn’t help, because this disease means there is no LDL receptor!

Question 19

Familial Defective Apo B-100

Answer 19

Phenotype

 - LDL-C levels increase 1.5 to 2-fold (160-300mg/dL)
 - Premature coronary heart disease

Genotype

  - POINT MUTATION in gene for apo B  (causing apo B to not be able to bind to the LDL receptor)
  - This is just change in one amino acid, but it is a crucial change in amino acid that is needed for apo B to bind to the LDL Receptor

Prevalance
-1/700 to 1/1000 (heterozygotes)

Treatment
-TLC; statins; statins plus niacin and/or Bile acid sequesterants

Note: The LDL Receptor in the liver normally binds to the apoB-100 and apoE. Recall the pathway of LDL that is produced from liver and returns.

First: Nascent VLDL (has apoB100,E, and C) carries
mainly triglycerides and also cholesterol from liver

Next: HDL donates more apoC, and apoE to make it
VLDL (it’s mature now and has apoB, E, C still)

Third: Extra hepatic/mainly adipose tissues have lipoprotein lipase that takes off/hydrolyzes the triglycerides, and then VLDL donates apoC back to HDL to turn itself into IDL=VLDL remanent (containing some triglycerides and cholester still, but now only ApoB-100 and apoE).

Finally: The remaining Triglycerides are lost along with apoE, so now it becomes LDL (and only contains cholesterol along with apoB-100)

This means that (for people with this disease) the IDL(VLDL-remanent) can still be taken up by Liver since it has apoE (along with defective apoB-100) to bind with LDL receptor on liver. However, the LDL can’t be taken up by liver since it lost the apoE now and only has the defective apoB-100. This is why there is a specific increase in LDL-C only!

Question 20

Polygenic Hypercholesterolemia (very common, so be ready if you are a family doctor!)

Answer 20

Phenotype

- LDL-C greater than 190mg/dL (about 2-fold)
- Coronary heart disease 3x to 4x general population

Genotype
-mutations in multiple genes (often poor diet)

Prevalance

 - 1/10 to 1/20 depending on age (very common)
 - So the prevalance increases with age, because it's COMBINATION of genes and diet and both disease increases with age as well as the progression gets more severe/has impact with age and diet.

Treatment
-TLC; statins; statins plus Bile acid sequestrants and/or niacin if necessary.

Question 21

LDL-Receptor Mutations

Answer 21

Class 1 - Null alleles, no detectable receptor
Class 2 - Slow/no processing of receptor, transport
deficient
Class 3 - Defective ligand binding, normal maturation
and transport
Class 4 - Internalization-defective, fails to localize in
coated pits
Class 5 - Recycling-defective, cannot return to cell
surface, degraded in endosome

Question 22

stopped at 44 mn also review prev card in video

Answer 22

finish only 5 min